NIH Research Festival
Mitochondrial hepatopathy is present in up to 20% of patients with mitochondrial disease. In addition to triggering mitochondrial hepatopathy, infection may also lead to potentially fatal episodes of metabolic decompensation characterized by lactic acidosis, hypoglycemia, and liver dysfunction/failure. The mechanism underlying this disruption of metabolic equilibrium in mitochondrial hepatopathy during infection is not clear. Previously, our group has shown that the immune system modulates hepatic metabolism during systemic immune activation. To examine the role of immune activation in precipitating metabolic decompensation in mitochondrial hepatopathy, we infected a mouse model of mitochondrial hepatopathy (LivCox10-/-) with mouse-adapted influenza (H1N1 PR8). In response to infection, Cox10-/- mice developed increased plasma lactate, enlarged mitochondria, and fatty liver. A cytokine profile of influenza-induced immune response revealed significant elevations of TNF-alpha. In targeting TNF-alpha in vivo using etanercept, a TNF-alpha antagonist, Cox10-/- mice demonstrated an improvement in hepatic phenotype indicated by a reduction in lipid accumulation. Our findings suggest that during influenza infection, TNF-alpha exacerbates underlying metabolic dysfunction in mitochondrial hepatopathy. The resolution of metabolic perturbations by etanercept suggests that targeting the immune system may be a viable strategy for alleviating the complications associated with metabolic decompensation.
Scientific Focus Area: Molecular Biology and Biochemistry
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